Microglial receptor TREM2 orchestrates an early immune response to neuronal stress in a mouse model of Alzheimer's disease Victoria E. von Saucken1, Taylor R. Jay2, Gary E. Landreth1* 1Stark Neurosciences Research Institute, Indiana University School of Medicine; 2Department of Neuroscience, Case Western Reserve University, School of Medicine *Corresponding Author (email@example.com)
Genetic studies identified loss-of-function variants of 'triggering receptor expressed on myeloid cells 2' (TREM2) as a strong risk factor for developing Alzheimer's disease (AD) and other neurodegenerative diseases. It is known that TREM2 signaling mediates the recruitment and survival of microglia to beta-amyloid plaques in the AD brain. However, the critical question remains of how the loss of TREM2 function in microglia predisposes the brain to AD pathology. We hypothesize that the loss of TREM2 impairs microglial sensing of damaged neurons early in disease that is associated with the progressive neuronal dysfunction and cell death observed in this disease. To assess the role of TREM2 in neuron-microglia interactions at the earliest stages of the disease, we compared TREM2 expressing and TREM2 deficient microglia in the 5XFAD AD mouse model at 1 month of age, before the onset of plaque deposition. Using immunohistochemistry, we observed extensive engagement of microglial processes with neuronal cell bodies and neurites exhibiting intra-neuronal amyloid accumulation. Less neuronal-microglial contacts were observed on nearby neurons without amyloid. We found significantly reduced neuron-microglia interactions in TREM2 deficient mice. These data suggest TREM2 deficient microglia have an impaired response to stressed, amyloid-laden neurons prior to plaque deposition. We also found that the lack of TREM2 modulates the levels of the synaptic proteins, synaptophysin and PSD95, in a brain region and cortical layer specific manner. These TREM2 mediated synaptic changes before plaque onset are reflective of the critical role of TREM2 in homeostatic monitoring of neurons by microglia, which may contribute to neuronal decline later in disease.
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